Cannabinoid Receptor Agonists for Treatment of Chronic Pain

描述（由申请人提供）：慢性疼痛可以由各种疾病引起，大约45%的美国人寻求治疗疼痛的医疗帮助。神经性疼痛是一种非常难以治疗的慢性疼痛，大多数患者没有得到充分的缓解。治疗炎症和疼痛的一个有希望的治疗药物靶点是大麻素CB2受体。在该提案的I期，我们的重点将是先导模板的结构优化，以开发具有疼痛抑制潜力且无中枢神经系统副作用的高效CB2选择性激动剂。已建立的体内和体外药理学试验将用于鉴定以下化合物：1)对CB2比CB1受体具有高选择性；2)结合和激活CB2受体具有高效、强效性；3)在逆转异常性疼痛（即在正常情况下对非有害刺激作出的伤害性行为）方面具有高疗效；4)在整个动物中没有大麻模拟副作用，这些副作用通常表明CB1受体激活。本课题的长期目标是开发一种既安全又有效的治疗慢性疼痛的新药。

DESCRIPTION (provided by applicant): Chronic pain can result from various disease conditions and about 45% of the U. S. population seeks medical help for treatment of pain. Neuropathic pain is a type of chronic pain which is very difficult to treat, and most patients do not get adequate relief. A promising therapeutic drug target for the treatment of inflammation and pain is the cannabinoid CB2 receptor. In Phase I of this proposal our focus will be on the structural optimization of our lead template to develop a high efficacy CB2 selective agonist with pain suppression potential and with no CNS side effects. Established in vivo and in vitro pharmacological assays will be used to identify compounds that: 1) are highly selective for CB2 over CB1 receptors; 2) possess high efficacy and high potency in binding and activating the CB2 receptor; 3) possess high efficacy in reversing allodynia (i.e., nociceptive behavior in response to normally non-noxious stimuli); and 4) lack cannabimimetic side effects in whole animals that are typically indicative of CB1 receptor activation. The long-term objective of this proposal is to develop a novel drug for treatment of chronic pain which is both safe and effective.